NEUROPSYCHIATRY DSM (PYDI 0416) — FALL, 1999 MEDICINAL CHEMISTRY OF — DR. RILEY

A. INTRODUCTION

Antipsychotic (neuroleptic) agents are primarily used in the therapy of schizophrenia, organic psychoses, the manic phase of manic-depressive illness and other acute or chronic idiopathic psychotic illnesses.

B. MECHANISM OF ACTION

Evidence supports the hypothesis that the etiology of psychotic disorders lies in neurochemical defects of and pathways in the brain. This hypothesis is supported by the fact that the primary pharmacological action of antipschotic agents is antagonism of and/or receptor in the CNS.

A development-based classification of drugs:

Order of binding affinity for CNS NT receptors

Classical Antipsychotics () D2 . D1 > "1 . 5HT2 Atypical (SDA) Antipsychotics

• First-generation () D2 > D1 . 5HT2 > "1 • Second-generation (, ) D2 . 5HT2 >> D1 > "1

1 Dopamine Biosynthesis and Catabolism

NH2 hydroxylase HO NH2

COOH O , Fe2+, FAH COOH HO 2 4 HO (rate limiting) L-Tyrosine L-Dihydroxyphenyl- alanine (L-DOPA)

L-Aromatic amino Pyridoxal acid decarboxylase phosphate (L-AAAD)

H OH Dopamine HO MAO HO NH2 HO NH2 COOH b-hydroxylase

HO Aldehyde HO HO oxidase Dopamine 3,4-Dihydromandelic acid R-

Catechol O-methyl Catechol O-methyl SAM transferase transferase

CH3O CH3O NH2 COOH MAO

HO Aldehyde HO oxidase

2 Serotonin Biosynthesis and Catabolism

NH 2 NH2 COOH hydroxylase 5 HO COOH (rate limiting) N N H H L-Tryptophan L-5-Hydroxytryptophan Aromatic Amino Acid Decarboxylase

NH2 CHO HO MAO HO

N N H H 5-Hydroxyindoleacetaldehyde 5-Hydroxytryptamine (5-HT, (5-HIA) serotonin)

Aldehyde oxidase CHO HO

N H 5-Hydroxyindoleacetic Acid (5-HIAA)

3 C. ANTIPSYCHOTIC DRUG CLASSES

PHENOTHIAZINE DERIVATIVES

• The first-used class of efficacious antipsychotic agents – , the prototypical member of this class, was first used to treat mental disease in 1951. • Nonselective DA-receptor antagonists; also act at other neurotransmitter receptors giving rise

to significiant AR profiles 9 S 1. Structural Properties 10 2 heterocycle N X • phenothiazine or bioisosteric heterocycle • a connector alkyl (side) chain terminated by • an aliphatic 3E-amine function Alkyl connector o NR2 3 -amine

2. Physicochemical Properties

• the phenothiazine heterocycle confers a high degree of lipophilicity on these antipsychotics which is balanced (solubility) by the cationized (at physiologic pH) amine function • the phenothiazines possess two potentially basic functional groups: 10 < the N -amine which is very weakly basic (pKb >10) because of the electron- withdrawing effects of the 2 rings attached to it and is not appreciably cationized at phys. pH, < the side chain tertiary amine function which confers strong organic basicity on the antipsychotic phenothiazines.

S S

+ H3O N X N X

H + NR2 NR2

• H2O solubility of the AP phenothiazines is increased for oral dosage formulation by treatment with an acid:

S S

HCl N X N X

H + - NR2 NR2 Cl

4 • conversely, the H2O soly of these drugs can be reduced through the formation of bioreversible hydrocarbon esters () thereby lowering dissolution rates and facilitating formulation of long-acting (1%3 weeks) depot injections:

S S

Prodrug Design N CF3 N CF3 Bioactivation

N N O N N OH OC(CH2)nCH3

Fluphenazine enanthate: n = 5 (1-2 wks.) Fluphenazine decanoate: n = 8 (2-3 wks) (tid and qid)

3. Structure-activity Relationships

• structural/steric complementarity has been demonstrated between the phenothiazines and the CNS neurotransmitter dopamine providing an explanation for the ability of the antipsychotic molecules to interact in an antagonistic fashion with DA–receptors:

A = phenothiazine antipsychotic

B = dopamine

C = superposition of phenothiazine and dopamine structures (note complementarity of Ar rings and basic amine functions)

D = superposition of phenothiazine (with alkylamine side chain oriented in opposite direction) – not lack of complementarity of basic amine functions

5 • structural modification of the phenothiazines:

(1) bioisosteres - derived by replacing the N-CH2 structural feature of the phenothiazines with a bioisosteric double bond:

S S

N X X

H Bioisosteres NR2 NR2

Phenothiazine Thioxanthene (cis > trans)

(2) addition of an electronegative atoms/group at C2 of the phenothiazine ring enhances antipsychotic potency, e.g.:

X = SO2NR2 > CF3 > COCH3 > Cl

(3) a 3-carbon alkyl connector between phenothiazine heterocycle and terminal 3E-amine function is optimal for dopamine-receptor blockade and antipsychotic activity. Shortening of the chain to 2-carbons results in a change in receptor affinity from DA to CNS receptors.

S S

N X N X

NR2 NR2 Antidopaminergic Antihistaminic

6 (4) Structural modification of the side chain amine function yields three AP phenothiazine subclasses:

N N N N

R N N N NR2 N R R

Aliphatic pheno- Piperidine pheno- pheno- tiazine derivatives tiazine derivatives tiazine derivatives

(5) pharmacologic/therapeutic profiles of these 3 classes of antipsychotics differ as follows:

Antipsychotic potency: > piperidines > aliphatics EPS frequency: piperazines > piperidines > aliphatics Sedation: aliphatics . piperidines > piperazines Hypotension: aliphatics > piperidines > piperazines

4. Biotransformation of the Antipsychotic Phenothiazines

• as depicted, several different biotransformation O reactions occur for the same phenothiazine molecule, numerous metabolites are formed and excreted, S • the 7-OH metabolite is an active antidopaminergic while the sulfoxide (S=O) metabolite is inactive [O] [O] • note than the thioxanthene derivatives do not form 7 S aromatic hydroxylated metabolites • metabolic pathways are significantly altered by a variety of factors (age, sex, interaction with other drugs, route N X of administration, etc.)

OND R N R

7 4. Therapeutic Phenothiazines S

N X R Aliphatic and Piperidine Phenothiazines

Name R = X =

Chlorpromazine (CH2)3N(CH3)2 Cl

Triflupromazine (CH2)3N(CH3)2 CF3

Promazine (CH2)3N(CH3)2 H ()

Thioridazine SCH3 SOCH3 (CH2 )2 N

CH3 OH Piperactazine COCH3 (CH2 )2 N Cl

S

N X

CH2CH2CH2 N N R Piperazine Phenothiazines

Name R = X =

Prochlorperazine CH3 Cl

Fluphenazine (CH2)2OH CF3

Trifluoperazine CH3 CF3

Acetophenazine (CH2)2OH COCH3

Thiethylperazine (CH2)2OH SCH2CH3

8 HETEROCYCLIC ANALOGUES OF THE PHENOTHIAZINES

Structural Class Structure

Thioxanthenes S < olefin bioisosteres of the phenothiazines < e.g. Thiothixene SO2NH2

H N

NCH3

Arylbutylpiperidines Decanoate < potent D2 receptor antagonists OH ester < two structural variants: O 1) Fluorobutyrophenone N () Cl 2) Diarylbutylpiperidine F () Haloperidol and Decanoate F O NH N

N

F Pimozide

Dihydroindolones < Molindone Hydrochloride Cl- O H C2H5

+ N CH3 O N H

9 Structural Class Structure

Dibenzazepines < four structural variants CH3 H3C N 1) Dibenzoxazepine (X=O) + H 4' N COOH () 4' -OOC 2) Dibenzodiazepine (X=NH) N N (Clozapine) N N 11 8 3) (X=S) Cl 2 8 2 Cl () N 4) Thienobenzodiazepine O H (X=NH) Loxapine succinate Clozapine

CH3 HOCH CH OCH CH 2 2 2 2 + H N N COOH 4' -OOC N N N N

N CH3 S S H Quetiapine fumarate

Benzisoxazoles < Risperidone F

O N Cl- O N + N H

CH3 N

10 ARYLBUTYLPIPERIDINES

• Structural Variants: piperidine O R Phenone butyl N NR2 R 3o-amine Ar N p-fluoro F 4C = butyro Ar Flurobutyrophenone diaryl Diarylbutylpiperidine

• Physicochemical Properties < lipophilic

< basic (3E-amine) - forms H2O-soluble salts

O O H + - NR2 HX NR2 X

F F

• Structure-activity Relationships

< para-F or similar electronegative substituent (e.g. CF3) provides maximal potency, < lengthening, shortening or branching of the butyro (4 carbon) chain decreases neuroleptic potency, < terminal basic amine function may vary in structure but is usually incorporated in a 6- membered heterocyclic ring < replacement of the C=O function with a CH-Ar structural feature yields therapeutically- useful antipsychotics (e.g. pimozide)

• Metabolism [H] O OND R N R

F

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• A class of neuroleptics that utilizes the heterocycle as a basic structural feature, • The dibenzazepine heterocycle is a lipophilic structure with very weakly basic properties, • Structural variants of dibenzazepines: < Dibenzoxazepine (X = O) < Dibenzodiazepine (X = NH) < Dibenzothiazepine (X=S) 4' < Piperazine substitution at C-11 providing a center (N ) of basicity for H2O-solubilizing salt formation to facilitate oral dosage formulation

Aromatic (imine) N Piperazine 10 N 11

Dibenzazepine 8 2 heterocycle 5 X bioisostere

may be NH, O, S

X = NH: dibenzdiazepine X = O: dibenzoxazepine X = S: dibenzothiazepine

• atypical antipsychotics: • clozapine • quetiapine • olanzapine

12 RISPERIDONE

• a derivative with high affinity for central serotonergic 5-HT2, dopaminergic D2 (SDA ratio . 5) and adrenergic "1-receptors in vivo • has improved efficacy vs. both positive (delusions and hallucinations) and negative (diminished emotions, low motivation) symptoms of schizophrenia and reduced EPS • HCl salt used for oral formulation

F

O - N Cl O + N N H

CH3 N

• Metabolism

(1) Alicyclic hydroxyation ([O]) – the 9-OH metabolite is a potent (2) Oxidative N-dealkylation (OD) (3) Benzisoxazole ring cleavage

F

[O] O N O ring scission N 1 8 N 9 [O] OD 7 CH3 N 5

F

HO O R

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